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Caspase-9 swings both ways in the apoptosome
Chu-Chiao Wu1, Shawn B Bratton1
1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center , Smithville, TX, USA.
Abstract:
For nearly 2 decades, investigators have debated whether cysteinyl-aspartate-specific protease 9 (caspase-9) is activated within the apoptotic protease-activating factor 1 (Apaf-1) apoptosome through proximity-induced homodimerization or through formation of a holoenzyme. Recently, we have demonstrated that caspase-9 forms (and likely transitions between) both caspase-9 homo- and Apaf-1:caspase-9 heterodimers, each of which plays unique roles in the recruitment and activation of caspase-9.
Insights
Caspase-9 activation in the apoptosome involves both homodimers and Apaf-1 heterodimers. These distinct caspase-9 complexes play unique roles in apoptosis, clarifying a long-standing biological debate.
Area of Science:
- Cellular biology
- Molecular mechanisms of apoptosis
Background:
- The activation mechanism of caspase-9 within the apoptosome has been debated for two decades.
- Key questions involve whether activation occurs via homodimerization or holoenzyme formation.
Purpose of the Study:
- To investigate the specific molecular complexes formed by caspase-9 during apoptosome assembly.
- To elucidate the distinct functional roles of these complexes in caspase-9 activation.
Main Methods:
- Analysis of caspase-9 complex formation within the Apaf-1 apoptosome.
- Characterization of homo- and heterodimeric caspase-9 species.
Main Results:
- Demonstrated that caspase-9 forms both homodimers and Apaf-1:caspase-9 heterodimers.
- Showed that these distinct complexes likely transition between each other.
- Identified unique roles for each complex in caspase-9 recruitment and activation.
Conclusions:
- Caspase-9 activation is mediated by a dynamic equilibrium of homo- and heterodimeric complexes.
- These findings resolve the long-standing debate on caspase-9 activation mechanisms within the apoptosome.